Previous work by the applicants has extensively documented the presence of sex differences in thrombosis and vasospasm, mainly in rodent species. These gender differences suggest that the increased incidence of atherosclerotic disease and myocardial infarction in men compared to women might be related to basic physiological differences in hemostatic function and fascular reactivity between the sexes. Furthermore, our studies have demonstrated that endogenous sex hormones are a potential cause of cardiovascular sex differences in non-primate species. A limitation of our earlier studies has been the use of primarily ordents and dogs as experimental models. We now propose to extend ourstudies to the non-human primate cynomolgus monkey (Macaca fascicularis). Our long-term objective is to identify the fundamental mechanisms which result in the observed gender differences in cardiovascular disease, and to provide a scientific basis for therapeutic manipulation of these differences. The specific aims for the current, five-year period include a) the extension to the non-human primate, of our previous comparisons of coronary vascular reactivity and platelet function in males and females, b) systematic evaluation of regional differences in contractile and relaxant responses to vasoactive substances in the primate coronary tree, as well as in other selected major circulations, c) determinatio of the extent to which the endothelium modifies smooth muscle contraction and relaxation in the primate coronary vessels and other major vessels, d) comparison of coronary reactivity and reactivity of other major vessels of male and female primates in the presence and absence of the endothelium, e) evaluation of the effects of androgen, estrogen and castration on the reactivity of intact and de-endothelialized isolated vessels, particularly in the coronary bed, and f) angiographic confirmation, in vivo, of in vitro vascular reactivitiy results, including the effects of gender. The major thrust of this proposal is not the documentation of sex-related disease processes per se, but rather the investigation, in primates, of underlying, physioloigcal, sex-related differences involved in pathogenesis of cardiovascular disease. These studies will result in an integrted picture of primate vascular reactivity, and will extend our earlier work on the role of gender and gonadal hormones in vasospasm and platelet function to a primate species.